Field of the Present Disclosure
The present disclosure relates to a MRI (magnetic resonance imaging) contrast agent containing a gadolinium complex, and, more particularly, to a DO3A-tranexamic acid compound having a structure of a chemical formula 1, or an ester compound thereof, and gadolinium complexes thereof.
Research Sponsored by Korean Government
The present disclosure is sponsored by Future Creation Science division of Korean Government under a subject No. 2013029618 which is supervised by Korean Research Institute, which belongs to a category “Key Search Support Project”, whose title is “HIGH SENSITIVITY CT MOLECULAR IMAGING NANOCOMPOSITE HAVING MULTI-ENERGY BANDWIDTH”, and which is conducted by Kyungpook National University (KNU) Industry-academic cooperation foundation between May 1, 2013 and Apr. 30, 2014.
Further, the present disclosure is sponsored by Future Creation Science division of Korean Government under a subject No. 2013069507 which is supervised by Korean Research Institute, which belongs to a category “Fundamental Search Project”, whose title is “GADOLINIUM NANOSTRUCTURES FOR NEUTRON CAPTURE THERAPY”, and which is conducted by Kyungpook National University Industry-academic cooperation foundation between Dec. 1, 2013 and Oct. 31, 2014.
Discussion of the Related Art
A MRI (magnetic resonance imaging) has been one of the most powerful techniques for non-invasive diagnosis of human anatomy, physiology and pathophysiology based on an excellent spatial resolution and contrast. Currently, a number of MRI techniques use Gd (III) complexes to increase a water proton relaxation rate in the human body to improve the image contrast. Typical advantages resulting from using the Gd (III) ions comes from unique properties such as a high magnetic moment of a long electron spin relaxation time. However, despite extensive and successful clinical applications thereof, most of conventional Gd (III) based contrast agents (GBCAs) are of an extracellular fluid (ECF) contrast agent with a rapid discharge from the kidney. Therefore, there is a need for a new MRI contrast agent having enhanced performance and specific functionality at the same time. A lot of effort has been devoted to develop a new class of MRI contrast agents for use as an organ targeting MRI contrast agent.
A liver-specific MRI contrast agent is divided into following two categories: (i) a hepatobiliary-specific contrast agent and (ii) reticuloendothelial cell- specific (or nano-particulate) contrast agent. The former contrast agent is absorbed by functional liver cells and released into a bile, and causes the reduction of a longitudinal relaxation time (T1) of the liver and bile tree due to their paramagnetic properties. Currently available contrast agents of this class are based on a Gd-chelate such as Gd-EOB-DTPA (Primovist®) and Gd-BOPTA (Multihance®). When injected, they are initially distributed in the ECF CAs compartment and is subsequently absorbed by the liver cells (hepatocytes). On the other hand, the latter contrast agent targets Kupffer's cells in the endothelial-based system, where phagocytosis of the contrast agent occurs, and an iron ions effect leads to reduction of the liver signal intensity to express a “black” liver instead of a “white” liver that is typically observed in the liver cell-specific contrast agent.

The present applicants have recently synthesized gadolinium complexes of several DO3A-tranexamate (2a-b, Chart 1) and reported that they exhibit hepatobiliary-specific properties (Gu, S.; Kim, H. K.; Lee, G. H.; Kang, B. S.; Chang, Y.; Kim, T. J. J. Med. Chem. 2011, 54, 143.). These observations and recent researches for multi-functional contrast agents have motivated the present applicants to produce several additional DO3A-tranexamates (1c-e) and their corresponding Gd-complexes (2c-e) for use as a new class of a liver-specific contrast agent. The present applicants also have analyzed SAR (structure-activity relationship) for a liver-specificity.